Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors

细菌蛋白合成抑制剂的合成平台

• 批准号: 9978836
• 负责人: Ian Bass Seiple
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978836
• 关键词: Address; Antibiotics; Architecture; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Biological; Chemicals; Collaborations; Complex; Daptomycin; Development; Funding; Goals; Human; Laboratories; Linezolid; Medical; Metabolic; Methods; Multi-Drug Resistance; National Institute of General Medical Sciences; Natural Products; Pharmaceutical Chemistry; Physicians; Prevalence; Property; Protein Synthesis Inhibitors; Research; Ribosomes; Streptogramins; Structure; Therapeutic; Toxic effect; analog; antimicrobial; base; frontier; improved; innovation; novel; novel therapeutics; operation; pathogenic bacteria; programs; resistant strain; structural biology

Project Summary/Abstract Only two new structural classes of antibiotics, exemplified by daptomycin and linezolid, have been introduced to the market in the past 50 years. This dearth of novel antibiotics is not due to lack of new chemical matter; indeed, dozens or even hundreds of molecules with antimicrobial activity are discovered annually, but the majority of these are not suitable for deployment as human therapeutics. Additionally, many of the antibiotics on the market have undesirable properties (e.g., toxicity, chemical instability, metabolic liabilities) that deter physicians from employing them. The high degree of structural complexity present in most of these molecules complicates medicinal chemistry efforts to improve their properties. Our laboratory seeks to address this challenge by developing modular strategies for the assembly of structurally complex classes of antibiotics that have not yet reached their potential as therapeutics. Unlike many total synthesis proposals, our primary goal is not to develop methods for the synthesis of natural products (although this can be accomplished with our approach), but rather to use their structural architectures to guide the development of new structural classes. During our first 2 years in operation, we have developed a modular, scalable synthesis of streptogramin antibiotics (J. Am. Chem. Soc. 2017, doi: 10.1021/jacs.7b08577), and we have made significant headway towards a practical synthesis of lankacidin antibiotics. With these preliminary results as groundwork, five years of NIGMS MIRA funding will enable the development structurally novel therapeutics based on these classes that have improved physicochemical properties, broader spectra of activity, and increased activity against multidrug-resistant strains of bacteria. This pursuit will be facilitated by chemical and biological innovations with broad applicability. We also propose a method for binding-induced hybridization of therapeutics that we believe will find use beyond the application to ribosome-targeting antibiotics. Our efforts will be enabled by strategic collaborations to enable crystallographic characterization of the binding interactions of our analogs (with Prof. Yury Polikanov, UIC) and to evaluate the efficacy of antibiotic candidates against a broad panel of bacterial pathogens, including many multi-drug resistant strains (with Dr. Dean Shinabarger, Micromyx). This research program is significant because it has the potential to expand the frontiers of chemical reactivity, to facilitate discoveries in structural biology, and to address an urgent unmet medical need.

项目摘要/摘要 仅引入了daptomycin和linezolid的例证的两种新的结构类抗生素类别 在过去的50年中进入市场。这种新型抗生素的缺乏并不是由于缺乏新的化学物质。 实际上，每年发现数十个具有抗菌活性的分子甚至数百个分子，但是 其中大多数不适合作为人类疗法部署。此外，许多抗生素 在市场上具有不良特性（例如毒性，化学不稳定性，代谢负债） 医生雇用它们。大多数这些分子中存在的高度结构复杂性 使药物化学的努力复杂化，以改善其性质。我们的实验室寻求解决这个问题 通过制定模块化策略来组装结构复杂的抗生素类别的挑战 尚未发挥他们的治疗潜力。与许多总体合成建议不同，我们的主要目标是 不开发合成天然产品的方法（尽管这可以通过我们的 方法），而是使用其结构体系结构来指导新结构类别的发展。 在运营的最初两年中，我们开发了链霉素的模块化，可扩展的合成 抗生素（J.Am。Chem。Soc。2017，doi：10.1021/jacs.7b08577），我们取得了重大的进展 实现Lankacidin抗生素的实际合成。以这些初步结果为基础，五年 Nigms Mira资金将基于这些类别的结构新颖的治疗剂 提高了理化特性，更广泛的活性光谱以及对 多种细菌抗性菌株。化学和生物创新将促进这种追求 广泛的适用性。我们还提出了一种结合诱导的疗法杂交的方法，我们认为 将发现超越核糖体靶向抗生素的应用。我们的努力将通过战略来实现 协作以实现我们类似物的结合相互作用的晶体学表征（与教授 尤里·波利卡诺夫（Yury Polikanov） 病原体，包括许多多药抗性菌株（Micromyx Dean Shinabarger博士）。 该研究计划很重要，因为它有可能扩大化学反应性的边界， 促进结构生物学的发现，并满足紧急未满足的医疗需求。